1. Technical Field of the Invention
This invention relates to controlled release drug dosage forms. More particularly it relates to a controlled release drug dosage form wherein the drug is released by diffusion in an acid pH environment and by disintegration in an environment of higher pH.
2. The Prior Art
The preparation of drugs for oral administration in specialized dosage forms known variously as controlled delivery systems, sustained release, timed disintegration, etc., is widely used. One of the most advantageous, for many reasons, is the 2-piece hard gelatin capsule filled with drug in the form of a multiplicity of pellets so prepared that they release the drug for absorption by a diffusion process. A variation is the inclusion of such pellets in compressed tablets.
This type of formulation is limited to drugs which are sufficiently water soluble. Many commonly used drugs which could be, and in fact are, used in this way have sufficient water solubility or are water soluble salts of amines or other molecules which can form soluble salts with acidic materials. However, as they move down the gastrointestinal tract, with rising pH they are converted to the free amines. These amines in many cases may still be sufficiently water soluble to continue to be released from the pellets by a diffusion process.
Where a drug is of a water insoluble type, pellets having a disintegration release mechanism may be formulated. The disintegration mechanism may be actuated by, for example, pH changes or enzymatic activity or both in the gastrointestinal tract.
However, a problem comes about for certain drugs, typically amine salts which are water soluble and remain water soluble in the acidic gastric fluid to which they are first exposed after ingestion. Alternatively, they may be capable of forming water soluble salts in the acidic gastric fluid. But as they move down the gastrointestinal tract and encounter higher pH fluids they revert to very sparingly soluble, or practically water insoluble, form. In any event the water solubility of the free base is so low it is then inadequate for a diffusion rate controlled release process.
The mobility of both the hydrogen and hydroxyl ions are so much greater than that of the larger drug molecules, that dialytic membranes which are barriers to these larger drug molecules and which are suitable for reducing the transmission of these molecules to useable rates, are practically no barrier at all to the hydrogen or hydroxyl ion. The pH of the interior of the pellet therefore becomes very quickly the same as that of the digestive fluid in which it is immersed. This means that it does not matter whether the formulator starts with an amine salt or a free amine. The digestive fluid pH will determine whether it remains in soluble salt form, or is converted to the soluble salt form when in acidic gastric fluid. Similarly, the drug will revert to its sparingly soluble free amine form as the pellet moves down the gastrointestinal tract to regions of higher pH.
A typical example of such behavior is the cardiac antiarrhythmic drug quinidine. It is usually used in the form of one of its water soluble salts such as the gluconate or the sulfate. These salts are readily water soluble. However, the gluconate for example, which has a solubility of about 140 mg/ml of water at 25.degree. C., falls to about 2 mg/ml at pH 7.5, and at pH 8.0, which may also be possible in the gastrointestinal tract, the solubility falls even lower, to about 0.4 mg/ml. All attempts to use a pure diffusion system have failed to produce a useful product. When the salt is converted to the free base the release process, for all practical purposes, stops. The total amount of drug that becomes available to the body for absorption under these conditions is erratic and rarely exceeds 50% of that present in the dosage form.
Another illustration of this type of problem is the cardiac drug dipyridamole. This is readily soluble in acid solutions. Pellets containing this drug and covered by a retarding dialytic membrane of satisfactory permeability for the drug, readily permit the passage of hydrogen ion to form a water soluble salt of the dipyridamole. But here again, further along in the gastrointestinal tract at higher pH values the release by diffusion ceases. Even if all of the original dipyridamole had been converted initially by gastric acidity to a soluble salt it would later revert to its free base. This inadequately soluble form will not diffuse at a useful rate through the retarding dialytic membrane which was of adequate permeability for the water soluble form of the drug.
It would be very useful to have a controlled release dosage form which could release drugs throughout the entire pH range found in the gastrointestinal tract because some drugs change markedly in solubility with pH. They are soluble in acidic media but only sparingly soluble, or practically insoluble, at higher pH values. This invention relates to such a controlled release system.